Current Understanding Regarding the Glioma Microenvironment and Impact of the Immune System

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Review of Neuroglia manuscript

This review by Demir E. et. al. attempts to summarize the present status of available information on glioma tumor microenvironment (TME) and its implications to glioma immunotherapy.  A short summary of published literature is given with salient features of TME in terms of glioma-associated Tregs, NK cells, neutrophils and macrophages with their implications to various immunotherapies such as checkpoint inhibitors, CAR T cells, tumor vaccines and oncolytic viral therapies are presented.  One stated main points in the Introduction, viz., “The glioma TME represents the interaction of tumor cells with neuronal and glial cells….”, however, is left undiscussed.  Recent studies (Monje M. et. al.; Venkataramani V. et al.) have shown the importance of glioma-normal brain interactions as important in determining glioma response to therapy. Inclusion of this aspect may make the review a bot stronger.  As it stands, it does not present major strengths.

Author Response

Review of Neuroglia manuscript

This review by Demir E. et. al. attempts to summarize the present status of available information on glioma tumor microenvironment (TME) and its implications to glioma immunotherapy.  A short summary of published literature is given with salient features of TME in terms of glioma-associated Tregs, NK cells, neutrophils and macrophages with their implications to various immunotherapies such as checkpoint inhibitors, CAR T cells, tumor vaccines and oncolytic viral therapies are presented.  One stated main points in the Introduction, viz., “The glioma TME represents the interaction of tumor cells with neuronal and glial cells….”, however, is left undiscussed.  Recent studies (Monje M. et. al.; Venkataramani V. et al.) have shown the importance of glioma-normal brain interactions as important in determining glioma response to therapy. Inclusion of this aspect may make the review a bot stronger.  As it stands, it does not present major strengths.

We thank the reviewer for their comments.  We have added further sections regarding the recommended citations and others to further discuss the glioma-normal brain interaction. This includes an entire new section of ~1000 words with appropriate references.

Reviewer 2 Report

Comments and Suggestions for Authors

The manuscript investigates the role of the tumor microenvironment (TME) in gliomagenesis, with a specific focus on the involvement of different cell types and their associated signaling pathways in the pathogenesis of high-grade gliomas (HGG). The paper is well-structured and effectively addresses crucial aspects, including the various components of the TME, the diversity of immune cells involved, and potential therapeutic strategies targeting these cells.

Minor Revisions

1. Line 61
   Original: “GSCs reside in close relationship with the vessels in a perivascular niche indicating an association with increased angiogenesis and invasiveness.”

Revision: While GSCs are identified as residing in a perivascular niche, they are also present in hypoxic niches, where they have distinct functions. Revise the text to include the role of GSCs in hypoxic niches and their contributions to tumor progression.

2. Line 143
   Original: “Targeting of VEGF has ultimately not been shown clinically to improve overall survival, despite improvements in imaging progression and reduced blood-brain-barrier leakiness.”

Revision: The sentence could be more precise, and additional context about VEGF targeting and BBB leakiness is needed.

3. Line 145
   Original: “In addition to the perivascular TME, the periarteriolar TME has been suggested as a unique environment, closer in structure to the hematopoietic cells of the bone marrow, which has unique signaling characteristics differentiating it from the perivascular TME.”

Revision: The phrase “unique signaling characteristics” requires elaboration. Expand on the specific signaling characteristics of the periarteriolar TME that differentiate them from the perivascular TME.

4. Line 402
   Original: “Table 2. Selected research studies involving immunotherapy trials in HGG.”

Revision: Update the table to reflect the most recent data, as the current last assessment (September 28, 2021 - table legend) appears outdated for a 2024/2025 publication. Also, the table is not referenced in the text, and several data columns are incomplete. Reference Table 2 in the text where relevant. Address the missing data in the columns “Sample Size,” “PFS,” “OS,” and “Year,” using terms like “not applicable,” “not addressed,” or “unknown” where appropriate.

5. Details on Specific Immunotherapy Trials – Table 2
   For the following immunotherapy approaches, provide more detail:
• “CDX-110 (rindopepimut)” and “Dendritic cell (DC)-based vaccine”
• Specify the patient population's clinical characteristics – was it conducted in GBM patients?
• “GVAX vaccine”
• Rephrase for clarity and indicate the disease where it was conducted.

Author Response

The manuscript investigates the role of the tumor microenvironment (TME) in gliomagenesis, with a specific focus on the involvement of different cell types and their associated signaling pathways in the pathogenesis of high-grade gliomas (HGG). The paper is well-structured and effectively addresses crucial aspects, including the various components of the TME, the diversity of immune cells involved, and potential therapeutic strategies targeting these cells.

We thank the reviewer for their comments and have made modifications below.

Minor Revisions

1. Line 61
   Original: “GSCs reside in close relationship with the vessels in a perivascular niche indicating an association with increased angiogenesis and invasiveness.”

Revision: While GSCs are identified as residing in a perivascular niche, they are also present in hypoxic niches, where they have distinct functions. Revise the text to include the role of GSCs in hypoxic niches and their contributions to tumor progression.

We have made this modification to line 61 and updated the references.

1. Line 143
   Original: “Targeting of VEGF has ultimately not been shown clinically to improve overall survival, despite improvements in imaging progression and reduced blood-brain-barrier leakiness.”

Revision: The sentence could be more precise, and additional context about VEGF targeting and BBB leakiness is needed.

This sentence is based on clinical trial data using Avastin and other VEGF inhibitors clinically. We have clarified this sentence to read “Patient treatment with VEGF inhibitors, such as bevacizumab, have ultimately not been shown clinically to improve overall survival despite improvements in progression free survival and reduced contrast enhancement, highlighting impact on the perivascular TME without durable survival benefit.”

1. Line 145
   Original: “In addition to the perivascular TME, the periarteriolar TME has been suggested as a unique environment, closer in structure to the hematopoietic cells of the bone marrow, which has unique signaling characteristics differentiating it from the perivascular TME.”

Revision: The phrase “unique signaling characteristics” requires elaboration. Expand on the specific signaling characteristics of the periarteriolar TME that differentiate them from the perivascular TME.

We have clarified this sentence further.

1. Line 402
   Original: “Table 2. Selected research studies involving immunotherapy trials in HGG.”

Revision: Update the table to reflect the most recent data, as the current last assessment (September 28, 2021 - table legend) appears outdated for a 2024/2025 publication. Also, the table is not referenced in the text, and several data columns are incomplete. Reference Table 2 in the text where relevant. Address the missing data in the columns “Sample Size,” “PFS,” “OS,” and “Year,” using terms like “not applicable,” “not addressed,” or “unknown” where appropriate.

We have updated the table to reflect the most recent information from these pivotal trials. These studies are not aimed to be an exhaustive list of all immunotherapy trials in glioma, but instead are the pivotal trials that also show best in class treatment of various targets. We have updated the table heading and cited the table in the text. Between 2021 and 2025, a total of 33 additional “immunotherapy” studies were listed on clinicaltrials.gov with no specific new-in-clas trial that was distinct from the current table.

1. Details on Specific Immunotherapy Trials – Table 2
   For the following immunotherapy approaches, provide more detail:
• “CDX-110 (rindopepimut)” and “Dendritic cell (DC)-based vaccine”
• Specify the patient population's clinical characteristics – was it conducted in GBM patients?

 

Yes this was in GBM, we have added this to the table.

 

• “GVAX vaccine”
• Rephrase for clarity and indicate the disease where it was conducted.

 

We have rephrased this

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The authors have addressed the queries raised on the previous submission.